Leukocyte Adhesion Deficiency Research Articles

The impact of Treosulfan-based conditioning for inborn errors of immunity: Is dose monitoring crucial?

In children with inborn errors of immunity (IEI) who will receive a hematopoietic stem cell transplant (HSCT) treosulfan-based conditioning is currently preferred. The aim of this study was to investigate early and late outcomes in pediatric IEI patients receiving pre-HSCT treosulfan and to examine the effect of treosulfan dose monitoring on outcomes. Seventy-three pediatric patients receiving this management between 2015 and 2022 were included. Overall survival rate was 80%, and event-free survival was 67.8%. A larger treosulfan dose AUC after first application increased the rate of early toxicity (p=.034) and slowed lymphocyte engraftment (r=.290; p=.030). Underlying disease, treosulfan AUC, donor type, stem cell type, number of immunosuppressive agents, the dose of anti-thymocyte globulin, and post-transplantation cyclophosphamide did not to increase risk of acute graft-versus-host disease. The risk of mixed chimerism (MC) in patients with autoimmune lymphoproliferative syndrome and leukocyte adhesion deficiency were higher than those with severe combined immunodeficiency (p=.021 and p=.014, respectively). The risk of MC was lower in those receiving peripheral blood stem cells (SC) compared with bone marrow derived SC (OR=.204, p=.022). The AUC of the treosulfan dose was not associated with poorer late outcomes. Treosulfan is an agent that can be used safely in the IEI patient group, level measurement appears essential to identify early toxicities. Prospective studies with more extended follow-up periods are needed.

Defective Treg generation and increased type 3 immune response in leukocyte adhesion deficiency 1

In 15 Turkish LAD-1 patients and controls, we assessed the impact of pathogenic ITGB2 mutations on Th17/Treg differentiation and functions, and innate lymphoid cell (ILC) subsets.The percentage of peripheral blood Treg cells, in vitro-generated induced Tregs differentiated from naive CD4+ T cells were decreased despite the elevated absolute counts of CD4+ cells in LAD-1 patients. Serum IL-23 levels were elevated in LAD-1 patients. Post-curdlan stimulation, LAD-1 patient-derived PBMCs produced more IL-17A. Additionally, the percentages of CD18-deficient Th17 cells expanded from total or naïve CD4+ T cells were higher. The blood ILC3 subset was significantly elevated in LAD-1. Finally, LAD-1 PBMCs showed defects in trans-well migration and proliferation and were more resistant to apoptosis.Defects in de novo generation of Tregs from CD18-deficient naïve T cells and elevated Th17s, and ILC3s in LAD-1 patients' peripheral blood suggest a type 3-skewed immunity and may contribute to LAD-1-associated autoimmune symptoms.

Improved Outcome Following Busulfan-Based Conditioning in Children with Functional Neutrophil Disorders Undergoing Hematopoietic Stem Cell Transplant from HLA-Matched Donors.

Hematopoietic stem-cell transplantation (HSCT) is the only curative treatment for chronic granulomatous disease (CGD) and leukocyte-adhesion deficiency (LAD), but both diseases have high rates of graft failure in transplant and patients with these diseases are often referred to HSCT with significant comorbidity. The intensity of the conditioning regimen should be balanced between the need to ensure durable engraftment and to minimize toxicity when transplanting young children with infections and organ damage. We report on 26 children transplanted at our institution with CGD and LAD over 24years. We found a higher incidence of graft failure in patients receiving treosulfan based conditioning for their first transplant. There was no effect of conditioning regimen on overall survival, as all 8 patients that proceeded to a second busulfan-based HSCT were salvaged. We recommend giving patients with CGD and LAD fully myeloablative conditioning with either a busulfan-based regimen or the combination of treosulfan, fludarabine, and thiotepa.

Rare and heterogeneous manifestations of leucocyte adhesion deficiency type 1: report of two cases with diagnostic dilemmas and novel ITGB2 mutation

BackgroundPrimary immunodeficiency disorders (PID) are rare disorders with heterogeneous manifestations, overlapping with other diseases such as autoimmunity, malignancy, and infections. This makes the diagnosis very challenging and delays management. Leucocyte adhesion defects (LAD) are a group of PIDs in which patients lack adhesion molecules on leukocytes needed for their emigration through blood vessels to the site of infection. Patients with LAD can present with diverse clinical features including severe and life-threatening infections, early in life, and the absence of pus formation around infection or inflammation. There is often delayed umbilical cord separation, omphalitis, late wound healing, and a high white blood cell count. If not recognized and managed early, can lead to life-threatening complications and death.Case PresentationLAD 1 is characterized by homozygous pathogenic variants in the integrin subunit beta 2 (ITGB2) gene. We report two cases of LAD1 with unusual presentations (post-circumcision excessive bleeding and chronic inflammation of the right eye) which were confirmed by flow cytometric analysis and genetic testing. We found two disease-causing ITGB2 pathogenic variants in both cases.ConclusionsThese cases highlight the importance of a multidisciplinary approach to recognizing clues in patients with uncommon manifestations of a rare disease. This approach initiates a proper diagnostic workup of primary immunodeficiency disorder leading to a better understanding of the disease, and appropriate patient counseling, and helps clinicians to be better equipped to deal with complications.

Clinical and Osteopetrosis-Like Radiological Findings in Patients with Leukocyte Adhesion Deficiency Type III.

Leukocyte and platelet integrin function defects are present in leukocyte adhesion deficiency type III (LAD-III) due to mutations in FERMT3. Additionally, osteoclast/osteoblast dysfunction develops in LAD-III. To discuss the distinguishing clinical, radiological, and laboratory features of LAD-III. This study included the clinical, radiological, and laboratory characteristics of twelve LAD-III patients. The male/female ratio was 8/4. The parental consanguinity ratio was 100%. Half of the patients had a family history of patients with similar findings. The median age at presentation and diagnosis was 18 (1-60) days and 6 (1-20) months, respectively. The median leukocyte count on admission was 43,150 (30,900-75,700)/μL. The absolute eosinophil count was tested in 8/12 patients, and eosinophilia was found in 6/8 (75%). All patients had a history of sepsis. Other severe infections were pneumonia (66.6%), omphalitis (25%), osteomyelitis (16.6%), gingivitis/periodontitis (16%), chorioretinitis (8.3%), otitis media (8.3%), diarrhea (8.3%), and palpebral conjunctiva infection (8.3%). Four patients (33.3%) received hematopoietic stem cell transplantation (HSCT) from HLA-matched-related donors, and one deceased after HSCT. At initial presentation, 4 (33.3%) patients were diagnosed with other hematologic disorders, three patients (P5, P7, and P8) with juvenile myelomonocytic leukemia (JMML), and one (P2) with myelodysplastic syndrome (MDS). In LAD-III, leukocytosis, eosinophilia, and bone marrow findings may mimic pathologies such as JMML and MDS. In addition to non-purulent infection susceptibility, patients with LAD-III exhibit Glanzmann-type bleeding disorder. In LAD-III, absent integrin activation due to kindlin-3 deficiency disrupts osteoclast actin cytoskeleton organization. This results in defective bone resorption and osteopetrosis-like radiological changes. These are distinctive features compared to other LAD types.

The Role of LFA-1 for the Differentiation and Function of Regulatory T Cells-Lessons Learned from Different Transgenic Mouse Models.

Regulatory T cells (Treg) are essential for the maintenance of peripheral tolerance. Treg dysfunction results in diverse inflammatory and autoimmune diseases with life-threatening consequences. β2-integrins (CD11a-d/CD18) play important roles in the migration of leukocytes into inflamed tissues and cell signaling. Of all β2-integrins, T cells, including Treg, only express CD11a/CD18, termed lymphocyte function-associated antigen 1 (LFA-1), on their surface. In humans, loss-of-function mutations in the common subunit CD18 result in leukocyte adhesion deficiency type-1 (LAD-1). Clinical symptoms vary depending on the extent of residual β2-integrin function, and patients may experience leukocytosis and recurrent infections. Some patients can develop autoimmune diseases, but the immune processes underlying the paradoxical situation of immune deficiency and autoimmunity have been scarcely investigated. To understand this complex phenotype, different transgenic mouse strains with a constitutive knockout of β2-integrins have been established. However, since a constitutive knockout affects all leukocytes and may limit the validity of studies focusing on their cell type-specific role, we established a Treg-specific CD18-floxed mouse strain. This mini-review aims to delineate the role of LFA-1 for the induction, maintenance, and regulatory function of Treg in vitro and in vivo as deduced from observations using the various β2-integrin-deficient mouse models.

A fatal yet salvageable inborn error – leukocyte adhesion deficiency

Leukocyte adhesion deficiency (LAD) Type 1 is a rare inborn error in infants characterized by delayed umbilical cord detachment, non-healing ulcers, and leukocytosis. Initially, knowledge of LAD was limited to the impairment of granulocyte function due to the scarcity of cases. However, as more and more cases are being reported, the knowledge of the bio-physiology of white blood cells, platelets, and various intercellular reactivity and signaling provides a new perception of this disease. We present a 17-day-old female child who presented with complaints of fever and redness in the perianal region and popliteal fossa. Investigations showed leukocytosis in blood and cerebrospinal fluid (CSF), raised C-Reactive Protein (CRP), and Pseudomonas-positive blood and CSF culture. Flow cytometry revealed the absence of CD18, CD11a, and CD11c. Aggressive antimicrobial agents were started; however, the baby died on day 30 of life. In this report, we emphasize the essential investigations needed for early diagnosis and effective precautions through which we can decrease the fatality rate of this rare disorder.

Genetic Load of Mutations Causing Inherited Diseases and Its Classification in Dairy Cattle Bred in the Russian Federation

This review addresses the concept of genetic load from the point of view of molecular genetics, development and efforts in selective breeding. As typical examples, the assessment of animals in the Holstein breed and its high-blooded crossbreeds is considered for mutations that cause three inherited diseases: bovine leukocyte adhesion deficiency (CD18 locus), complex vertebral malformation (SLC35A3 locus), and brachyspina (FANCI locus). The reasons for their occurrence and accumulation in the breeding herds of the black-pied genealogical root are discussed. These include an intense artificial-selection of bulls and cows in highly productive herds and the intensive sale (within and between countries) of breeding material (animals, semen, embryos) from a small population of sires from countries with a high level of dairy-cattle breeding development. There is a founder effect when the source of mutant-allele spread is a prominent sire. For example, the greatest contribution to the spread of mutant alleles CD18G, SLC35A3T and FANCIBY was made by the descendants of three closely related bulls. A genogeographic generalization of the mutation occurrence in the world and Russia is provided for these hereditary-disease loci and, includes a total of 31 countries where these mutations were detected. The genetic-load classification for these and other mutations is given. The mutations are inherited both recessively (CD18G, SLC35A3T, FANCIBY) and codominantly (CSN3A, CSN3C, CSN3E, CSN2A1, CSN2B). Genetic load is classified into the following types: mutational, segregation, substitutional, and immigration. For each of these, examples are given that explain their occurrence. Overall, it can be concluded that the phenomenon of genetic load in industrial herds of dairy cattle requires special attention when creating healthy livestock and obtaining high-quality dairy products.

Hematologically important mutations: Leukocyte adhesion deficiency (second update)

Leukocyte adhesion deficiency (LAD) is an immunodeficiency caused by defects in the adhesion of leukocytes (especially neutrophils) to the blood vessel wall. As a result, patients with LAD suffer from severe bacterial infections and impaired wound healing, accompanied by neutrophilia. In LAD-I, characterized directly after birth by delayed separation of the umbilical cord, mutations are found in ITGB2, the gene that encodes the β subunit (CD18) of the β2 integrins. In the rare LAD-II disease, the fucosylation of selectin ligands is disturbed, caused by mutations in SLC35C1, the gene that encodes a GDP-fucose transporter of the Golgi system. LAD-II patients lack the H and Lewis Lea and Leb blood group antigens. Finally, in LAD-III, the conformational activation of the hematopoietically expressed β integrins is disturbed, leading to leukocyte and platelet dysfunction. This last syndrome is caused by mutations in FERMT3, encoding the kindlin-3 protein in all blood cells, involved in the regulation of β integrin conformation. This article contains an update of the mutations that we consider to be relevant for the various forms of LAD.

A Novel Deletion in FERMT3 Causes LAD-III in a Turkish Family.

Leukocyte adhesion deficiency-III (LAD-III) is an extremely rare autosomal recessive syndrome caused by mutations in FERMT3, the gene encoding kindlin-3. The genetic alterations in this gene lead to abnormal expression or activity of kindlin-3 in leukocytes and platelets. Kindlin-3 acts as an important regulator of integrin activation. LAD-III has features of the bleeding syndrome of Glanzmann and also of leukocyte adhesion deficiency. In this study, we report on two families, one of Turkish and one of Syrian origin, with clinical features of LAD-III, loss of kindlin-3 protein expression, and a functional leukocyte defect. A novel, homozygous deletion in FERMT3 (c.921delC, p.Ser307Argfs*21) was found in the Turkish patient. The parents were carriers of the mutation, consistent with an autosomal recessive inheritance. A common c.1525C > T (p.Arg509*) mutation was found in the Syrian patient. In conclusion, beside the variant c.1525C > T in the FERMT3 gene, which was previously found in more than 15 patients in Anatolia, our study is the first to identify the novel homozygous variant c.921delC in the FERMT3 gene.

Phosphorylation Regulation Mechanism of β2 Integrin for the Binding of Filamin Revealed by Markov State Model.

Leukocyte adhesion deficiency-1 (LAD-1) disorder is a severe immunodeficiency syndrome caused by deficiency or mutation of β2 integrin. The phosphorylation on threonine 758 of β2 integrin acts as a molecular switch inhibiting the binding of filamin. However, the switch mechanism of site-specific phosphorylation at the atom level is still poorly understood. To resolve the regulation mechanism, all-atom molecular dynamics simulation and Markov state model were used to study the dynamic regulation pathway of phosphorylation. Wild type system possessed lower binding free energy and fewer number of states than the phosphorylated system. Both systems underwent local disorder-to-order conformation conversion when achieving steady states. To reach steady states, wild type adopted less number of transition paths/shortest path according to the transition path theory than the phosphorylated system. The underlying phosphorylated regulation pathway was from P1 to P0 and then P4 state, and the main driving force should be hydrogen bond and hydrophobic interaction disturbing the secondary structure of phosphorylated states. These studies will shed light on the pathogenesis of LAD-1 disease and lay a foundation for drug development.

Periodontal Management of Leukocyte Adhesion Deficiency Type-I with Photodynamic Therapy-A Case Report

Leukocyte Adhesion Deficiency type I (LAD-I) is a rare autosomal recessive disorder affecting the immune system which is characterised by defects in white blood cell integrin receptors leading to impaired adhesion and chemotaxis with increased susceptibility to recurrent infections, delayed wound healing, and periodontitis. A case of aggressive form of generalised periodontitis in a 19- year-old girl with LAD-I is presented in this case report. The medical diagnosis was made on the basis of characteristic clinical and laboratory findings suggestive of LAD, particularly the total absence of Cluster of Differentiation (CD)18, CD11a, CD11b, and CD11c which were determined by flow cytometry. After non surgical periodontal therapy, photodynamic therapy with Low Level Laser Therapy (LLT) was performed. After 3 months, reduced inflammatory signs and improved periodontal health was observed. This report highlights the importance of the differential diagnosis of severe immunodeficiency disorders. It also emphasises the joint role of medical and dental specialists to control oral infections and thereby preventing tooth loss.

Impaired Treg-DC interactions contribute to autoimmunity in leukocyte adhesion deficiency type 1.

Leukocyte adhesion deficiency type 1 (LAD-1) is a rare disease resulting from mutations in the gene encoding for the common β-chain of the β2-integrin family (CD18). The most prominent clinical symptoms are profound leukocytosis and high susceptibility to infections. Patients with LAD-1 are prone to develop autoimmune diseases, but the molecular and cellular mechanisms that result in coexisting immunodeficiency and autoimmunity are still unresolved. CD4+FOXP3+ Treg are known for their essential role in preventing autoimmunity. To understand the role of Treg in LAD-1 development and manifestation of autoimmunity, we generated mice specifically lacking CD18 on Treg (CD18Foxp3), resulting in defective LFA-1 expression. Here, we demonstrate a crucial role of LFA-1 on Treg to maintain immune homeostasis by modifying T cell-DC interactions and CD4+ T cell activation. Treg-specific CD18 deletion did not impair Treg migration into extralymphatic organs, but it resulted in shorter interactions of Treg with DC. In vivo, CD18Foxp3 mice developed spontaneous hyperplasia in lymphatic organs and diffuse inflammation of the skin and in multiple internal organs. Thus, LFA-1 on Treg is required for the maintenance of immune homeostasis.

GENETICALLY CONFIRMED TYPE I LEUKOCYTE ADHESION DEFICIENCY IN A TWO-YEAR-OLD MALE

<h3>Introduction</h3> Leukocyte adhesion deficiency (LAD) type 1 affects about one in a million people world-wide. Presentation typically includes delayed separation of the umbilical cord, neutrophilia, and repeated bacterial infections soon after birth. Here we present a case of a 2-year-old male who presented in respiratory failure later found to have genetically confirmed type 1 LAD. <h3>Case Description</h3> A 2-year-old male in state custody presented to an outside hospital with fever and respiratory distress secondary to croup. Hospital course was complicated by right vocal cord avulsion likely secondary to trauma, difficulty in extubation requiring steroids and tracheostomy, persistent leukocytosis with neutrophilia, and reccuring fevers. He was transferred to our hospital after CD18/CDb11 expression was found to be 0%. We sent primary immunodeficiency genetic testing confirming a pathogenic variant in ITGB2 and 22q22.3 pathogenic deletion which included ITGB2, AIRE and ICOSLG. <h3>Discussion</h3> When given an unclassical and convoluted history, relying on more objective data like laboratory results and physical exam is crucial. Our case was challenging due to a complex social situation making obtaining a good history difficult and inability to examine the patient on initial consultation. History revealed insignificant infection history and no delayed separation of the umbilical cord. Therefore, before being able to examine the patient and obtain genetic testing there was some skepticism of the diagnosis despite supporting flow cytometry. Once the patient arrived at our facility, physical exam revealed wound healing characteristic of LAD, increasing suspicion of the disease. Genetic testing confirmed LAD, as he was hemizygous for a pathogenic variant in ITGB2.

Preclinical Evaluation of Foamy Virus Vector-Mediated Gene Addition in Human Hematopoietic Stem/Progenitor Cells for Correction of Leukocyte Adhesion Deficiency Type 1.

Ex vivo gene therapy procedures targeting hematopoietic stem and progenitor cells (HSPCs) predominantly utilize lentivirus-based vectors for gene transfer. We provide the first pre-clinical evidence of the therapeutic utility of a foamy virus vector (FVV) for the genetic correction of human leukocyte adhesion deficiency type 1 (LAD-1), an inherited primary immunodeficiency resulting from mutation of the β2 integrin common chain, CD18. CD34+ HSPCs isolated from a severely affected LAD-1 patient were transduced under a current good manufacturing practice-compatible protocol with FVV harboring a therapeutic CD18 transgene. LAD-1-associated cellular chemotactic defects were ameliorated in transgene-positive, myeloid-differentiated LAD-1 cells assayed in response to a strong neutrophil chemoattractant in vitro. Xenotransplantation of vector-transduced LAD-1 HSPCs in immunodeficient (NSG) mice resulted in long-term (∼5 months) human cell engraftment within murine bone marrow. Moreover, engrafted LAD-1 myeloid cells displayed in vivo levels of transgene marking previously reported to ameliorate the LAD-1 phenotype in a large animal model of the disease. Vector insertion site analysis revealed a favorable vector integration profile with no overt evidence of genotoxicity. These results coupled with the unique biological features of wild-type foamy virus support the development of FVVs for ex vivo gene therapy of LAD-1.

Sequence variants in the ITGB2 gene underlying leukocyte adhesion deficiency Type-1 in four consanguineous families

Integrins are integral transmembrane proteins involved in various biological activities. One such protein β2 integrin CD18, encoded by ITGB2 gene, is involved in leukocyte adhesion and wound healing. Leukocyte adhesion and crawling being the key process in combating infections are mainly facilitated by β2 integrins. Sequence variants in the ITGB2 gene cause leukocyte adhesion deficiency, type I (LAD1). To search for the disease-causing sequence variants in four patients with LAD1 born to four different consanguineous parents of Pakistani origin. Flow cytometry was used to measure CD18 levels. Genomic DNA was extracted from the blood of the patients, parents, and healthy siblings. Using exon-specific primers, the ITGB2 gene was Sanger sequenced. Clinical features including skin abscesses, delayed umbilical cord separation, mild omphalitis, and neutrophilia were recorded in the patients. Flow-cytometric analysis revealed highly reduced CD18 levels (< 2 %) in the patients. Sequence analysis of the ITGB2 gene revealed four disease-causing variants, including two novels [p.(Tyr130*), p.(Ala245Pro)], and two previously reported [p. (Cys62*), p.(Asp128Tyr)]. Identification of the LAD1 causative variants further expanded the mutation spectrum in the ITGB2 gene. This study will facilitate genetic counseling of the families carrying LAD1 type features in the Pakistani population.

Impairment of cytokine production following immunological synapse formation in patients with Wiskott-Aldrich syndrome and leukocyte adhesion deficiency type 1

T cells following immunological synapse (IS) formation with antigen-presenting cells produce multiple cytokines through T cell receptor, integrin, and costimulatory signaling. Here, we investigated the cytokine profiles following IS formation in response to staphylococcal superantigen exposure in three adolescent patients with classical Wiskott-Aldrich syndrome (WAS) and in one patient with leukocyte adhesion deficiency (LAD) type 1. All WAS patients showed lower Th1 and Th2-skewed cytokine production; similar results were observed in the flow cytometric analysis of IFNγ- and IL-4-producing T cells. The patient with LAD type 1 with somatic mosaicism in 2% of CD8+ T cells showed lower Th1 and Th2 cytokine production than healthy controls. The patients with WAS were susceptible to infections and atopic manifestations, and the patients with LAD type 1 showed cold abscess on their skin, our findings using patient samples provide clinical insights into the mechanisms underlying immunodeficiency related to the symptoms of each disease.

Preclinical safety and efficacy of lentiviral-mediated gene therapy for leukocyte adhesion deficiency type I

Leukocyte adhesion deficiency type I (LAD-I) is a primary immunodeficiency caused by mutations in the ITGB2 gene, which encodes for the CD18 subunit of β2-integrins. Deficient expression of β2-integrins results in impaired neutrophil migration in response to bacterial and fungal infections. Using a lentiviral vector (LV) that mediates a preferential myeloid expression of human CD18 (Chim.hCD18-LV), we first demonstrated that gene therapy efficiently corrected the phenotype of mice with severe LAD-I. Next, we investigated if the ectopic hCD18 expression modified the phenotypic characteristics of human healthy donor hematopoietic stem cells and their progeny. Significantly, transduction of healthy CD34+ cells with the Chim.hCD18-LV did not modify the membrane expression of CD18 nor the adhesion of physiological ligands to transduced cells. Additionally, we observed that the repopulating properties of healthy CD34+ cells were preserved following transduction with the Chim.hCD18-LV, and that a safe polyclonal repopulation pattern was observed in transplanted immunodeficient NOD scid gamma (NSG) mice. In a final set of experiments, we demonstrated that transduction of CD34+ cells from a severe LAD-I patient with the Chim.hCD18-LV restores the expression of β2-integrins in these cells. These results offer additional preclinical safety and efficacy evidence supporting the gene therapy of patients with severe LAD-I.

Leukocyte Adhesion Deficiency: First Case Report from Bangladesh

Leukocyte Adhesion Deficiency (LAD) is an autosomal recessive immunodeficiency disorder characterized by failure of leukocyte to adhere to endothelium resulting in recurrent overwhelming infection from childhood. Deficiency of CD18 expression due to mutation of beta-2 integrin results in LAD. Persistent neutrophilia without infection and leukemoid reaction during infection is hallmark for LAD. Based on percentage of CD18 expression it can be divided into three types (mild, moderate and severe). Diagnosis requires flow cytometric measurement of CD 18, CD11a, CD11b and CD15a or mutation analysis. We are presenting a 4-year female baby with recurrent skin and soft tissue infection. Diagnosis was suspected by history, physical examination and blood reports and confirmed by flow cytometric measurement of CD18 expression. It reveals LAD type-I severe variety. Allogenic stem cell transplant is the only recommended option for LAD. In other cases, antibiotic and antifungals are the mainstay of conservative management.

Healing With Complication: An Unusual Case of Nasal Tip Ulceration in Leukocyte Adhesion Deficiency Type 1

A 2-month-old girl presented with a necrotizing lesion over the tip of the nose that started as redness. The lesion subsequently increased in size to form a vesicle and ruptured to form a chronic, progressive, nonhealing ulcer without pus discharge (Figure 1, A). The girl was born at term, birth weight 2.5 kg. There was a history of delayed separation of the umbilical cord at day 22 of life. She developed an episode of omphalitis and another episode of sepsis with pneumonia on days 6 and 20 of life, respectively.